Molecular Determinants of Atherosclerotic Cardiovascular Disease in Multi-ethnic Populations

多种族人群动脉粥样硬化性心血管疾病的分子决定因素

• 批准号: 10650109
• 负责人: Bing Yu
• 金额: $ 78.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650109
• 关键词: African; African American population; Atherosclerosis; Atherosclerosis Risk in Communities; Biochemical Pathway; Bioinformatics; Biological; Biometry; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cloud Computing; Coronary Artery Risk Development in Young Adults Study; Coronary heart disease; Data; Development; Diet; Education; Elderly; Environment; Ethnic Origin; Ethnic Population; Etiology; European; Event; Exhibits; Framingham Heart Study; Functional disorder; Future; Genetic Determinism; Genomics; Goals; Hispanic Americans; Hispanic Community Health Study/Study of Latinos; Human; Impairment; Incidence; Individual; Inflammation; Inflammatory; Infrastructure; Intervention; Intervention Studies; Jackson Heart Study; Knowledge; Life Style; Link; Lipids; Measures; Mediating; Mendelian randomization; Metabolic; Metabolic dysfunction; Metabolism; Minority; Modeling; Molecular; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Pathway interactions; Physical activity; Positioning Attribute; Prevention; Process; Research; Resources; Risk Factors; Role; Single Nucleotide Polymorphism; Stroke; Technology; Testing; Time; Trans-Omics for Precision Medicine; Variant; Work; adjudication; atherosclerosis risk; biobank; burden of illness; cardiovascular disorder risk; clinical risk; coronary artery calcium; effective intervention; efficacious intervention; gene product; genetic architecture; genetic variant; genome sequencing; high risk; intimal medial thickening; metabolome; metabolomics; middle age; mortality; multi-ethnic; multiple omics; novel; oxidation; polygenic risk score; prevent; programs; secondary analysis; sex; social determinants; trait; whole genome

ABSTRACT Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide. Understanding the process of atherosclerosis and its progression is essential to decrease ASCVD burden. Despite successful identification of genetic variants and clinical risk factors related to ASCVD over the last decade, the underlying mechanism - how genetic variants and human metabolism contribute to atherosclerosis remains unclear. Circulating metabolites, the ultimate products of gene and environment interaction, holds promise to link genetic variants, circulating metabolites to atherosclerosis. We previous work has shown that circulating metabolites involved in lipids and oxidation metabolism and their genetic determinants predict the onset of ASCVD. Few studies have examined the metabolic influence on atherosclerosis in multi-ethnic populations, and the effect of longitudinal metabolomic changes on atherosclerosis. Our overall objective is to identify circulating metabolite and its longitudinal change, along with the genetic determinants, contributing to atherosclerosis and ASCVD in middle and late life among multi-ethnic populations. We propose to conduct this project in six studies from the Trans-Omics for Precision Medicine (TOPMed) Program, including European, African and Hispanic Americans. We will leverage the unique resources from each study on whole genome sequencing (WGS) data, metabolome profiles, and atherosclerotic traits, and use TOPMed Cloud Computing as the computational engine. Our aims are: (1) to identify circulating metabolite and it change associated with ASCVD risk; (2) to determine circulating metabolite and it change associated subclinical atherosclerosis and its progression; and (3) to characterize genetic architecture of ASCVD metabolites and evaluate its association with ASCVD risk. Our team is uniquely positioned, given our expertise in ASCVD pathophysiology, metabolome profiling, genomics, biostatistics and bioinformatics. The results of this research will enable continued scientific progress toward an understanding of ASCVD etiology, with direct implications for prevention and potential therapies.

摘要 动脉粥样硬化性心血管疾病（ASCVD）仍然是全球死亡的主要原因。理解 动脉粥样硬化的过程及其进展对于减少ASCVD负担是至关重要的。尽管成功 在过去十年中，与ASCVD相关的遗传变异和临床风险因素的确定， 机制-遗传变异和人体代谢如何导致动脉粥样硬化仍不清楚。 循环代谢产物是基因与环境相互作用的最终产物， 变异体、循环代谢物与动脉粥样硬化的关系。我们以前的工作表明，循环代谢物 参与脂质和氧化代谢及其遗传决定因素预测ASCVD的发病。几 研究已经检查了多种族人群中代谢对动脉粥样硬化的影响， 动脉粥样硬化的纵向代谢组学变化。我们的总体目标是确定循环代谢物 它的纵向变化，沿着遗传决定因素，有助于动脉粥样硬化和ASCVD， 多民族人口的中晚期生活。我们建议从以下六个方面进行这项研究： Trans-Omics for Precision Medicine（TOPMed）计划，包括欧洲，非洲和西班牙裔美国人。 我们将充分利用每项研究的独特资源，包括全基因组测序（WGS）数据、代谢组学数据、 配置文件和动脉粥样硬化的特点，并使用TOPMed云计算作为计算引擎。我们的目标 是：（1）确定循环代谢物及其与ASCVD风险相关的变化;（2）确定循环代谢物及其与ASCVD风险相关的变化。 代谢产物及其变化相关的亚临床动脉粥样硬化及其进展;和（3）表征 ASCVD代谢物的遗传结构，并评估其与ASCVD风险的相关性。我们的团队是独一无二的 定位，鉴于我们在ASCVD病理生理学，代谢组学分析，基因组学，生物统计学和 生物信息学这项研究的结果将使科学继续进步， ASCVD病因学，对预防和潜在治疗有直接影响。